11beta-hydroxy-17alpha-alkyl estrogens and intermediates in the production thereof



United States Patent 2,991,295 IIp-HYDROXY-lh-ALKY-L ESTROGENS AND INTERMEDIATES IN THE PRODUCTION THEREOF Barney J. Magerlein, Kalamazoo, and John A. Hogg,

Kalamazoo Township, Kalamazoo County, Micln, assignors to The Upjohn Company, Kalamazoo, Mich, a corporation of Michigan No Drawing. Filed Aug. 21, 1956, Ser. No. 605,442 *7 Claims. (Cl. 260-3975) This invention relates to steroid chemistry and is more particularly concerned with novel processes for the production of the physiologically active llfl-hydroxy-flaalkyl-l9-nortestosterones (U.S. 2,735,854) from steroids having an aromatic A-ring and to certain novel compounds produced thereby. It is an object of the present invention to provide the novel processes and compounds described herein which are useful in the production of 1 1 3-hydroxy-17 a-alkyl-19-nortestosterones. Other objects and uses will be apparent to one skilled in the art.

The process of this invention, illustrated by the following equation wherein R is alkyl and R 0 is an ether radical, comprises: reacting the 17-carbonyl group of 3 etherified 3,11 fl-dihydroxy-l,3,5 (l0)-estratrien-l7-one (I) with alkyl magnesium halide Grignard reagent to produce S-etherified 17a-a1ky1-l,3,5 10) -estratriene-3, 115,17/3-triol (II); chemically reducing the A-ring of the thus-obtained l7u-alkyl compound (II) with lithium, liquid ammonia and an alcohol to produce 3-etherified 17 a-alkyl-2,5(10)-estradiene,3,1lB-triol (III) and hydrolyzing and isomerizing the thus-obtained diene (III) by heating with an acid hydrolyzing agent to produce 11,8- hydroxy-17u-alky1-19-nortestosterone (IV). The 1113- hydroxy-17a-alkyl-l9-nortestosterone (IV) also can be obtained from B-etherified 17a-alkyl-2,5(l0)-estradiene- 3,115,17B-triol (III) by reacting with an acid hydrolyzing agent at room temperature to produce l7u-alkyl-11 @1718- dihydroxy-S (10)-estren-3-one and isomen'zing the (10)- double bond of the thus-obtained 3-keto compound by reacting with a base OH: CH3

0 OH H HO HO I RaO- 2 I II CH: CH:

OH OH LQ nofj HO 1 IV III (e.g. sodium methoxide in methanol, sodium hydroxide in ethanol, etc.) or by heating with an acid hydrolyzing agent. The starting 3-etherified 3,l1;3-dihydroxy-1,3,5 (10)-estratrien-l7-one (I) is prepared as described in copending application Serial No. 406,364, filed January 26, 1954. e

In the processes of the present invention the exact nature of the ether radical (R 0 in the foregoing equation) is immaterial, but generally said ether radical con tains less than forty atoms. Preferably said radical is hydrocarbonoxy [hydrocarbonO-] containing less than twelve carbon atoms. In an especially preferred embodiment of this invention said radical is alkoxy containing less than nine carbon atoms. The most preferred embodiment of said radical is methoxy. Illustrative ether.

radicals are methoxy, ethoxy, propoxy, butyroxy, valerhexyl, heptyl, octyl, isooctyl, etc.

In carrying out the process of the present invention 3 etherified 3,l1fl-dihydroxy-1,3,5(10)-estratrien-17-one (I) is alkylated by the Grignard method at the l7-carbon= atom by heating with alkyl magnesium halide Grignard i reagent (e.g. methyl bromide or iodide, ethyl chloride; bromide, or iodide, etc.) using a suitable solvent (e.g.l

ether, benzene, toluene, etc.) to produce 3-etherified 17aalkyl-l,3,5,(l0)-estratriene-3,115,17/3-triol (II), the hydrolysis of the Grignard addition compound being carried out according to conventional prior art procedure as illustrated by the preferred procedures of Examples 1 and 2; the l7a-alkylation can also be conducted by using an alkyl compound for the Grignard reagent;-

and this method is sometimes preferred. The 3-etherified' 170a alkyl-1,3,5(10)-estratriene-3,1 1,8,17fi-t1'i01 (II) a lower-alkanol containing less than six carbon atoms,

e.g. methanol, ethanol, isopropanol, etc. andliquid ammonia, a solvent (e.g. tetrahydrofuran, dioxane, etc.)

being employed when necessary to obtain a homogeneous solution, to produce 3-etherified ;17a-alkyl-2,5(10)-estradiene-3,1lp,17fi-triol (III), preferred procedures being given in Example 3 and 4. Hydrolyzing and isomerizing B-etherified 17c'c-alkyl-2,5(10)-estradiene-3,1 lB,17,B-triol 7 (III) to obtain 1lfi-hydroxy-17o -alkyl-19-nortestosterone" (IV) is accomplished (preferred procedures in Examples 5 and 6) by heating (suitably 65 to degrees centigrade) suitably for fifteen minutes to four hours with "an acid hydrolyzing agent, e.g. aqueous mineral acid (eg.

dilute sulfuric acid or the preferred dilute hydrochloric acid, etc.) or aqueous organic acid (e. g.' fifty percent f aqueous acetic acid, aqueous formic acid, etc.) of suitable acid strength using, if necessarygan organic solvent (clglf methanol, ethanol, dioxane, etc.) to obtain a homogene ous reaction mixture, the shorter reactionperiods and/or;

lower reaction temperatures usually being preferred when mineral acids are employed. The isolation and purification of the compounds of the foredescribed processesis; procedures i s re edi accomplished by conventional by Examples 1 through 6. t I The following examples are illustrative only and not to be construed as limiting the scope of the present invention.

Illustrative alkyl radi I cals are methyl, ethyl, propyl, butyl, isobutyl, pent yl;

is chemically reduced by the Birch reduction method with-j lithium (or sodium or potassium), an alcohol (preferably Example 1 17a-methyl-3-methoxy-1,3,5(10) -estratriene- 11,8,17fi-dil same solvent provides highly purified material melting at 159 to 161 degrees centigrade.

Analysis-Calculated for C H O C, 75.91; H, 8.92.

Found: C; H.

Example 2. 1 7a-ethyl-3-metlzoxy-1,3,5 (10) -estratriene- 115,1 7 fl-diol By substituting ethyl magnesium bromide (or iodide) for the methyl magnesium bromide in the procedure of Example 1, the starting 3-methoxy-1,3,5(10)-estratrien- 17-one is alkylated to produce 17a-ethyl-3-methoxy-L3, 5(10)-estratriene-11,8,17 3-di0l. The crude 17a-ethyl compound is isolated and purified in the same manner as described for the corresponding flat-methyl compound in Example 1.

In the same manner as shown in Examples 1 and 2, other B-ethenfied 3,11;3dihydroxy-1,3,5( -estratrien-17- ones are converted to other S-etherified 17a-alkyl-1,3,5 (10)-estratriene-3,l1/3,l7fi-triols by reacting with the appropriate alkyl magnesium halide, including those wherein the 3-ether, alkyl, and halide radicals are those specified in the foregoing description.

Example 3 1 7a-methyl-3-methoxy-2 ,5 (10 -estradiene- 115,175-dz'0l A solution of 380 milligrams of l7a-methyl-3-methoxy- 1,3,5(10)-estratriene-l113,175-dio1 in ten milliliters of dioxane, eighty milliliters of liquid ammonia, and 2.5 milliliters of ethanol is prepared and 250 milligrams of lithium metal is added. After the lithium metal has reacted the solvent is evaporated from the resulting solution. Water then is added to the residue and the product is extracted with methylene dichloride. Evaporation of the methylene dichloride solvent provides crude crystalline 17a. methyl 3-methoxy-2,5(10)-estradiene-1*15,17fi-dio1. Pure product is obtained by recrystallization from ethyl acetate-hexane (Skellysolve B).

Example 4. 17a-ethyl-3-methoxy-2,5 (10)-estradiene- 115,1 7,8-diol A solution of 17a-ethyl-3-methoxy-1,3,5(10)-estratriene-llflJZB-diol in dioxane, liquid ammonia, and ethanol reacted with lithium metal according to the procedure of Example 3 provides 17ot-ethyl-3-methoxy-2,5,

(10)-estradiene-11,8,17p-diol.

Following the procedures of Examples 3 and 4, other 3- etherified 17a-alkyl-1,3,5(10)-estratriene-3,115,17,8-trio1s are chemically reduced to other S-etherified 17u'alkyl- 2,5( 10) -estradiene-3,1 113,17p-triols, including those wherein the 3-ether and Not-alkyl radicals are those specified in the foregoing description.

Example 5. 11 fi-hydroxy-l 7a-methyl-19-n0rtest0s1erone The crude crystalline 17a-methyl-3-methoxy-2,5(10)- estradiene-11fl,17fl-diol obtained according to the procedure of Example 3 is dissolved in twenty milliliters of methanol containing two milliliters of water and one-half milliliter of concentrated hydrochloric acid. The resulting solution is heated under reflux for fifteen minutes. Then excess sodium acetate is added and the methanol distilled under vacuum. The product is extracted tom the residue with methylene dichloride. Evaporation of the methylene dichloride solvent provides milligrams of 1lp-hydroxy-17a-methyl-19-nortestosterone melting at 216 to 222 degrees centigrade. Recrystallization from ethyl acetate gives purified product melting at 219 to 224 degrees centigrade.

Analysis.--Calculated for C H O C, 74.96; H, 9.27. Found: C, 74.92; H, 9.36.

Example 6'. l1 fi-hydroxy-Ih-ethyl-l 9 rzortestosterone Treatment of l7a-ethyl-3-methoxy-2,5(10)-estradiene- 1113,17/3-diol with hydrochloric acid in aqueous methanol solution according to the procedure of Example 5 provides llfl-hydroxy-l7u-ethyl-l9-nortestosterone, melting point 164 to 167 degrees centigrade.

In the same manner as shown in Examples 5 and 6, other 3-etherified l7a-alkyl-2,5( 10)-estradiene-3,1 15,17fltriols are hydrolyzed and isomerized by heating with hydrochloric acid in aqueous methanol to provide other 11,9- hydroxy-lh-alkyl-l9-nortestosterones, including those wherein the 3-ether and Not-alkyl radicals are those specified in the foregoing description.

It is to be understood that the invention is not to be limited to the exact details of operation or exact compounds shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.

We claim:

1. An unsaturated 3-etherified l7a-alkylestrane3,llfl, l7B-triol selected from the group consisting of compounds of the formulae CH: OH:

OH OH wherein R 0 is a hydrocarbonoxy radical containing less than twelve carbon atoms and R is an alkyl radical containing less than nine carbon atoms.

2. 3 etherified 17oz alkyl l,3,5(10) estratriene- 3,115,1718-triol wherein the 3-ether radical is alkoxy containing less than nine carbon atoms and the l7a-alkyl radical contains less than five carbon atoms.

3. 3 etherified 17a. alkyl 2,5 (10) estradiene 3, 115,17fi-triol wherein the 3-ether radical is alkoxy containing less than nine carbon atoms and the l7a-alkyl radical contains less than five carbon atoms.

4. 17 a-methyl-3-methoxy-1,3,5 l0) -estratriene-1 1 8,175- diol.

5. 17oz ethyl 3 methoxy 1,3,5 (10) estratriene- 115,175-diol.

6. 17a methyl 3 -methoxy 2,5(10) estradiene- 113,17B-diol.

7. 17a ethyl 3 methoxy 2,5(10) estradiene 11/3, 17/3-diol.

and

References Cited in the file of this patent UNITED STATES PATENTS 2,655,518 Colton Oct. 13, 1953 2,698,855 Hicks Jan. 4, 1955 2,735,854 Herr Feb. 21, 1956 2,744,122 Djerassi May 1, 1956 2,753,342 Djerassi July 3, 1956 2,774,775 Konnan Dec. 18, 1956 OTHER REFERENCES Fieser et aL: Natural Products Related to Phenanthrene, 3rd ed., 1949, Reinhold Pub. Corp., New York, p.376. 

1. AN UNSATURATED 3-ETHERIFIED 17A-ALKYLESTRANE-3, 11B, 17B-TRIOL SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS OF THE FORMULAE 